rs200179598

Variant names:

• chr9-131523011-C-T
• rs200179598
• NM_001077365.2:c.2083C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001077365.2(POMT1):​c.2083C>T​(p.Arg695Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000311 in 1,609,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R695H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: POMT1 NM_001077365.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.38
• Publications: 3 publications found

Genes affected

POMT1 (HGNC:9202): (protein O-mannosyltransferase 1) The protein encoded by this gene is an O-mannosyltransferase that requires interaction with the product of the POMT2 gene for enzymatic function. The encoded protein is found in the membrane of the endoplasmic reticulum. Defects in this gene are a cause of Walker-Warburg syndrome (WWS) and limb-girdle muscular dystrophy type 2K (LGMD2K). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2008]

POMT1 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Genomics England PanelApp, G2P
• myopathy caused by variation in POMT1

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive limb-girdle muscular dystrophy type 2K

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy without intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscle-eye-brain disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14276823).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077365.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT1	NM_001077365.2	MANE Select	c.2083C>T	p.Arg695Cys	missense	Exon 20 of 20	NP_001070833.1	A0A140VKE0
	POMT1	NM_001353193.2		c.2149C>T	p.Arg717Cys	missense	Exon 20 of 20	NP_001340122.2	Q9Y6A1-1
	POMT1	NM_007171.4		c.2149C>T	p.Arg717Cys	missense	Exon 20 of 20	NP_009102.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT1	ENST00000402686.8	TSL:1 MANE Select	c.2083C>T	p.Arg695Cys	missense	Exon 20 of 20	ENSP00000385797.4	Q9Y6A1-2
	POMT1	ENST00000372228.9	TSL:1	c.2149C>T	p.Arg717Cys	missense	Exon 20 of 20	ENSP00000361302.3	Q9Y6A1-1
	POMT1	ENST00000423007.6	TSL:1	c.2140C>T	p.Arg714Cys	missense	Exon 19 of 19	ENSP00000404119.2	A0A1V1FTP4

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000688 AC: 17 AN: 247174 AF XY: 0.0000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000624

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000309 AC: 45 AN: 1457286 Hom.: 0 Cov.: 34 AF XY: 0.0000331 AC XY: 24 AN XY: 724792

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.000180 AC: 8 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 85736

European-Finnish (FIN) AF: 0.0000384 AC: 2 AN: 52116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4182

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111402

Other (OTH) AF: 0.0000499 AC: 3 AN: 60168

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74482

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000121 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2K (1)
-	1	-	not provided (1)
-	1	-	Walker-Warburg congenital muscular dystrophy;C1836373:Autosomal recessive limb-girdle muscular dystrophy type 2K;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.23
Sift	Benign	0.21	T
Sift4G	Benign	0.16	T
Polyphen		0.0050	B
Vest4		0.12
MVP		0.82
MPC		0.33
ClinPred		0.079	T
GERP RS		2.6
Varity_R		0.10
gMVP		0.50
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200179598; hg19: chr9-134398398; COSMIC: COSV61227028; COSMIC: COSV61227028;